US4556659A - Substituted 9-(1-0- or 3-0-monosubstituted or 1,3-Di-0-substituted propoxymethyl)-purines as antiviral agents - Google Patents

Substituted 9-(1-0- or 3-0-monosubstituted or 1,3-Di-0-substituted propoxymethyl)-purines as antiviral agents Download PDF

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US4556659A
US4556659A US06406583 US40658382A US4556659A US 4556659 A US4556659 A US 4556659A US 06406583 US06406583 US 06406583 US 40658382 A US40658382 A US 40658382A US 4556659 A US4556659 A US 4556659A
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hydrogen
compound
propoxymethyl
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Julien P. H. Verheyden
John C. Martin
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Syntex (USA) Inc
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D473/00Heterocyclic compounds containing purine ring systems
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    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00Ethers; Compounds having groups, groups or groups
    • C07C43/02Ethers
    • C07C43/03Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14Unsaturated ethers
    • C07C43/17Unsaturated ethers containing halogen
    • C07C43/174Unsaturated ethers containing halogen containing six-membered aromatic rings
    • C07C43/1745Unsaturated ethers containing halogen containing six-membered aromatic rings having more than one ether bound
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00Ethers; Compounds having groups, groups or groups
    • C07C43/02Ethers
    • C07C43/03Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/14Unsaturated ethers
    • C07C43/178Unsaturated ethers containing hydroxy or O-metal groups
    • C07C43/1785Unsaturated ethers containing hydroxy or O-metal groups having more than one ether bound

Abstract

Compounds useful as antiviral agents are defined by the following formula: ##STR1## wherein R1 is hydrogen, --C(Y)OR7 or --C(O)NHR7 wherein R7 is alkyl of one to twelve carbon atoms, alkenyl of two to twelve carbon atoms, cyclopentyl, cyclohexyl, phenyl or benzyl;
R2 is --C(Y)OR7 or --C(O)NHR7 wherein R7 is as defined above;
Y is oxygen or sulfur;
R3 is hydrogen, halo, thio, lower alkylthio of one to six carbon atoms, azido, NR9 R10 wherein R9 and R10 are independently hydrogen or lower alkyl of one to six carbon atoms or --NHC(O)R8 wherein R8 is hydrogen, alkyl of one to nineteen carbon atoms or 1-adamantyl; and
(a) R6 is hydrogen, halo, lower alkoxy of one to six carbon atoms, azido, thio, lower alkylthio of one to six carbon atoms, --NR9 R10 wherein R9 and R10 are as defined above or --NHC(O)R8 wherein R8 is as defined above and R4 together with R5 is a bond; or
(b) R5 together with R6 is a keto group and R4 is hydrogen.

Description

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to substituted 9-(1-0- or 3-0-monosubstituted or 1,3-di-0-substituted-2-propoxymethyl)purines which are useful as antiviral agents. The invention also relates to a pharmaceutical composition containing the above compounds in combination with a suitable non-toxic excipient, the composition being useful in combatting viral infections. The invention also relates to a process for preparing the compounds of the invention.

2. Related Disclosure

Viral infections are widespread and result in a wide variety of symptoms. Some viral infections are easily overcome by the body's defense mechanism, but when this defense mechanism is impaired these infections can lead to permanent damage, e.g., blindness, and even to death. One such family of viruses which may cause serious infections is the herpes virus group.

The drugs presently used to treat viral infections are ineffective in many cases or, if effective, are needed in large and/or continuous dosages which produce serious side-effects and/or toxicity. Therefore there is a need for an effective antiviral agent which is effective at lower dosages than the presently available drugs, thus diminishing the chance of possible side-effects and toxicity.

U.S. Pat. No. 4,199,574 discloses compounds represented by the following generic formula: ##STR2## wherein X sulphur or oxygen, R1 is hydrogen, halogen, hydroxy, alkoxy, azide, thio, alkylthio, amino, alkylamino or dialkylamino; R2 is hydrogen, halogen, alkylthio, acylamino, amino or azide; R3 is hydrogen, straight or branch chain or cyclic alkyl, hydroxyalkyl, benzyloxyalkyl or phenyl; R4 is hydrogen, hydroxy or alkyl; R5 is hydrogen, hydroxy, amino, alkyl, hydroxyalkyl, benzyloxy, benzoyloxy, benzoyloxymethyl, sulphamoyloxy, phosphate, carboxypropiamyloxy, straight chain or cyclic acyloxy having from 1 to 8 carbon atoms e.g., acetoxy or substituted carbamoyl group of formula NHCO-Z wherein Z is alkyl, aryl or aralkyl optionally substituted by one or more of sulphonyl, amino, carbamoyl or halogen; R6 is hydrogen or alkyl, provided that when X is oxygen and R2, R3, R4, and R6 are hydrogen, R1 is not amino or methylamino when R5 is hydrogen or hydroxy, or a salt thereof.

The class of compounds represented by the above formula and the pharmaceutically acceptable acid addition salts thereof are described to exhibit antiviral activity. See also Tetrahedron Letters, 21, 327-30 (1980) and U.S. Pat. No. 4,294,831.

SUMMARY OF THE INVENTION

It has now been discovered that substituted 9-(1-0-or 3-0-monosubstituted or 1,3-di-0-substituted-1,3-dihydroxy-2-propoxymethyl)purines are particularly active antiviral agents.

The first aspect of the present invention is the compound of the following formula: ##STR3## wherein R1 is hydrogen, --C(Y)OR7 or --C(O)NHR7 wherein R7 is alkyl of one to twelve carbon atoms, alkenyl of two to twelve carbon atoms, cyclopentyl, cyclohexyl, phenyl or benzyl;

R2 is --C(Y)OR7 or --C(O)NHR7 wherein R7 is as defined above;

Y is oxygen or sulfur;

R3 is hydrogen, halo, thio, lower alkylthio of one to six carbon atoms, azido, NR9 R10 wherein R9 and R10 are independently hydrogen or lower alkyl of one to six carbon atoms or --NHC(O)R8 wherein R8 is hydrogen, alkyl of one to nineteen carbon atoms or 1-adamantyl; and

(a) R6 is hydrogen, halo, lower alkoxy of one to six carbon atoms, azido, thio, lower alkylthio of one to six carbon atoms, --NR9 R10 wherein R9 and R10 are as defined above or --NHC(O)R3 wherein R8 is as defined above and R4 together with R5 is a bond; or

(b) R5 together with R6 is a keto group and R4 is hydrogen.

Another aspect of the invention relates to a pharmaceutical composition for antiviral use comprising a compound of the instant invention and a suitable carrier.

A further aspect of the invention is a method of treating viral infections consisting of administering a compound of the present invention or a composition containing same.

Yet another aspect of the invention is a process for preparing the compounds of formula (I) which comprises

(a) reacting a dihydroxy compound of formula (X) or (XIV) wherein A is hydrogen (infra) with a dicarbonate of the formula (R7 OC(O))2 O wherein R7 is as defined above; or

(b) reacting an intermediate of the formula ##STR4## wherein W is hydrogen or 1-carbonylimidazole and Wa is 1-carbonylimidazole with the appropriate alcohol or amine; or

(c) reacting a compound of formula (XV)(supra) wherein W is hydrogen or 1-thiocarbonylimidazole and Wa is 1-thiocarbonylimidazole with the appropriate alcohol; or

(d) reacting the trityl protected derivative of formula (X) or (XIV) wherein A is hydrogen with a hydrocarbyloxycarbonyl chloride of the formula ClC(O)OR7 and removing the trityl protecting groups.

Yet another aspect of the invention is the novel compounds of formula (XV) which are useful as antiviral agents and as intermediates for the preparation of compounds of formula (I).

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS

As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated.

The term "hydrocarbyl" refers to substituents consisting solely of carbon and hydrogen. Examples of hydrocarbyl groups are alkyl, alkenyl, cyclopentyl, cyclohexyl, phenyl and benzyl.

The term "alkyl" refers to a straight or branched chain monovalent substituent consisting solely of carbon and hydrogen, containing no unsaturation and having one to twelve carbon atoms. Examples of alkyl are methyl, ethyl, propyl, t-butyl, hexyl, n-octyl, n-decyl, and n-dodecyl. The term "lower alkyl" refers to alkyl groups as defined above but containing one to six carbon atoms. The term "alkenyl" refers to a straight or branched chain monovalent substituent consisting solely of carbon and hydrogen, containing one double bond and having two to twelve carbon atoms. Examples of "alkenyl" are ethenyl, propenyl, i-butenyl, pentenyl, hexenyl and n-decenyl. The term "l-adamantyl" refers to the following ring structure. ##STR5## "Lower alkoxy" refers to "lower alkyl-O-" wherein "lower alkyl" is as defined above. Examples of "lower alkoxy" are methoxy, ethoxy, propoxy, i-butoxy, pentyloxy and n-hexyloxy. The term "lower alkylthio" refers to "lower alkyl-S-" wherein "lower alkyl" is as defined above. Examples of "lower alkylthio" are methylthio, n-propylthio, n-butylthio and n-pentylthio. "Thio" refers to -SH. "Amino" refers to -NH2. "Azido" refers to N3. "Halo" refers to fluoro, chloro and bromo. "Thiocarbonyl" refers to >C═S.

Compounds of formula (I) wherein R1 is hydrogen contain an assymetric carbon atom. Accordingly, these compounds may be prepared in either optically active form or as a racemic mixture. Unless otherwise specified, the compounds of formula (I) described herein are all in the racemic form. However, the scope of the subject invention is not to be considered limited to the racemic form, but to encompass the individual optical isomers of the compounds of formula (I).

It is to be understood that the definition of R5 together with R6 as keto includes the tautomeric hydroxy form but for convenience the keto form will be used to represent both tautomeric forms.

A preferred group of compounds of formula (I) is that wherein R3 is amino, R4 is hydrogen and R5 together with R6 is keto (compounds of formula (Ia) infra). Another preferred group of compounds of formula (I) is that wherein R3 is hydrogen or amino, R6 is hydrogen, thio or NH2 and R4 together with R5 is a bond with the proviso that R3 and R6 are not both hydrogen. A preferred subgroup within these groups is that wherein R1 and R2 are independently --C(O)OR7 and R7 is lower alkyl, particularly methyl.

UTILITY AND ADMINISTRATION

The subject compound of formula (I) and the pharmaceutically acceptable salts thereof exhibit potent antiviral activity when administered to warm blooded and cold blooded animals, particularly mammals, birds, and fish, but most particularly humans. For example, the compound of the present invention exhibits excellent activity against Herpes Simplex virus I and II and related viruses such as cytomegalovirus, Epstein-Barr virus and varicella Zoster virus.

Pharmaceutical compositions, both veterinary and human, containing the subject compound appropriate for antiviral use are prepared by methods and contain excipients which are well known in the art. A generally recognized compendium of such methods and ingredients is Remington's Pharmaceutical Sciences by E. W. Martin, (Mark Publ. Co., 15th Ed., 1975).

The compound of the invention may be administered parenterally (for example, by intraveneous, subcutaneous, intraperitoneal or intramuscular injection), orally, topically, rectally or intranasally.

The compositions are administered orally or parenterally at dose levels, calculated as the free base, of about 0.1 to 300 mg/kg, preferably 1.0 to 30 mg/kg of mammal body weight, and are used in man in a unit dosage form, administered one to five times daily in the amount of 1 to 500 mg per unit dose. For oral administration, fine powders or granules may contain diluting, dispersing and/or surface active agents, and may be presented in a draught, in water or in a syrup; in capsules or sachets in the dry state or in a non-aqueous solution or suspension, wherein suspending agents may be included; in tablets, wherein binders and lubricants may be included; in a suspension in water or a syrup; or in an aerosol. Where desirable or necessary, flavoring, preserving, suspending, thickening or emulsifying agents may be included. Tablets and granules are preferred, and these may be coated. The amount of compound of formula (I) in the formulation may vary from 0.1 percent weight (% w) to 99% w or more of the compound based on the total formulation and about 1% w to 99.9% w excipient. Preferably the compound is present at a level of 10%-95% w.

For parenteral administration or for administration as drops, as for eye infections, the compounds may be presented in aqueous solution in a concentration of from about 0.1 to 10%, more preferably about 0.1 to 7%. The solution may contain antioxidants, buffers, and other suitable additives.

Alternatively for infections of the eye, or other external tissues, e.g. mouth and skin, the compositions are preferably applied to the infected part of the body of the patient topically as an ointment, cream, aerosol or powder, preferably an an ointment or cream. The compounds may be presented in an ointment, for instance with a water soluble ointment base, or in a cream, for instance with an oil in water cream base, in a concentration of from about 0.01 to 10%; preferably 0.1 to 7%, most preferably about 3.0% w/v. Additionally, viral infections may be treated by use of a sustained release drug delivery system as is described in U.S. Pat. No. 4,217,898.

For aerosol administration, the active ingredient is preferably supplied in finely divided form along with a surfactant and a propellant. Typical percentages of active ingredients are 0.01 to 20% by weight, preferably 0.04 to 1.0%.

Surfactants must, of course, be non-toxic, and preferably soluble in the propellant. Representative of such agents are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olestearic and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride such as, for example, ethylene glycol, glycerol, erythritol, arabitol, mannitol, sorbitol, the hexitol anhydrides derived from sorbitol (the sorbitan esters sold under the trademark "Spans") and the polyoxyethylene and polyoxypropylene derivatives of these esters. Mixed esters, such as mixed or natural glycerides may be employed. The preferred surface-active agents are the oleates or sorbitan, e.g., those sold under the trademarks "Arlacel C" (Sorbitan sesquioleate), "Span 80" (sorbitan monooleate) and "Span 85" (sorbitan trioleate). The surfactant may constitute 0.1-20% by weight of the composition, preferably 0.25-5%.

The balance of the composition is ordinarly propellant. Liquefied propellants are typically gases at ambient conditions, and are condensed under pressure. Among suitable liquefied propellants are the lower alkanes containing up to five carbons, such as butane and propane; and preferably fluorinated or fluorochlorinated alkanes, such as are sold under the trademark "Freon." Mixtures of the above may also be employed.

In producing the aerosol, a container equipped with a suitable valve is filled with the appropriate propellant, containing the finely divided active ingredient and surfactant. The ingredients are thus maintained at an elevated pressure until released by action of the valve.

The compounds of the present invention or compositions containing same are also useful in treating non-human mammals, birds, e.g., chickens and turkeys, and cold-blooded animals, e.g., fish. For example, the compounds of the present invention and compositions containing same exhibit antiviral activity against the following non-human viruses:

Sciruid herpesvirus 1

Cavlid herpesvirus 1

Lagomorph herpesvirus 1

Phasianid herpesvirus 1

Phasianid herpesvirus 2 (Marek's disease)

Turkey herpesvirus 1

Anatid herpesvirus 1

Catfish herpesvirus 1

Equid herpesvirus 3

Bovid herpesvirus 1

Bovid herpesvirus 2

Bovid herpesvirus 3

Bovid herpesvirus 4

Pig herpesvirus 1

Pig herpesvirus 2

Murid herpesvirus 1

Cebid herpesvirus 1

Cebid herpesvirus 2

Tupaiid herpesvirus 1

Canine herpesvirus 1

Feline herpesvirus 1

Equid herpesvirus 1

Equid herpesvirus 2

Avian viral diseases such as Marek's disease and the like are prevented and/or treated by compounds of the present invention by methods well-known in the veterinary art such as by injecting the birds with the composition containing the compound, or by adding the compound of the instant invention to feed or drinking water.

Fish which are in a confined area such as a pool, aquarium or holding tank may also be treated for viral infections such as herpeslike viruses, e.g., channel catfish virus (CCV), herpes-virus salomones, Nerka virus and the like by adding the compound directly to the water of the pool, aquarium or holding tank or by incorporating the compounds into the feed.

The exact regimen for administration of the compounds and compositions disclosed herein will necessarily be dependent upon the needs of the individual subject being treated, the type of treatment and, of course, the judgement of the attending practitioner.

PREPARATION

The compounds of formula (I) may be prepared from compounds of formula (X) (infra) and compounds of formula (XIV) wherein A is hydrogen (infra) which compounds are prepared by Reaction Sequence Ib. Intermediate of formula (V), which is used in Reaction Sequence Ib, is prepared by Reaction Sequence Ia. ##STR6## wherein A is hydrogen or acetyl and R3 and R6 are defined in the following table:

______________________________________         R.sup.3   R.sup.6______________________________________(a)             NH.sub.2    OR(b)             NH.sub.2    SH(c)             N.sub.3     N.sub.3(d)             NH.sub.2    NH.sub.2(e)             Cl          NH.sub.2(f)             N.sub.3     NH.sub.2(g)             NH.sub.2    H(h)             H           NH.sub.2(i)             H           SH(j)             SH          NH.sub.2______________________________________

In Reaction Sequence Ia, the compound of formula (III) is prepared by adding epichlorohydrin (II) dropwise to a solution of an alkali metal salt, preferably the sodium salt, of optionally substituted benzyl alcohol in a solvent such as dimethylformamide, dimethylacetamide, hexamethylphosphoramide, dimethylsulfoxide, sulfolane, tetrahydrofuran, and dioxane at a temperature of about 0° C. to 100° C., preferably at about 15° c. to 40° C. The reaction mixture is stirred for about 10 hours to 24 hours, preferably for about 12 hours to 18 hours at a temperature of about 0° C. to 10° C., preferably from about 20° C. to 50° C.

Compound of formula (III) is chloromethylated to compound of formula (IV) by bubbling dry hydrogen chloride gas in a solution of the compound and paraformaldehyde dissolved in a halogenated hydrocarbon solvent such as dichloroethane, chloroform, dichloromethane, or 1,1,2-trichloroethane cooled to a temperature of about 0° C. to 25° C., preferably at a temperature of about 0° C. The hydrogen chloride gas is added over 30 minutes to 3 hours, preferably over 1 hour to 2 hours until the paraformaldehyde dissolves. The solution is held at a temperature from about 0° C. to 10° C. for about 12 hours to 48 hours, preferably from about 0° to 5° C. for about 16 hours to 24 hours.

Compound of formula (V) is prepared by reacting an alkali metal acetate such as sodium acetate with compound of formula (IV) dissolved in a solvent such as dimethylformamide, tetrahydrofuran, dimethylacetamide, hexamethylphosphoramide, dimethylsulfoxide, sulfolane, and dioxane at a temperature of about 0° C. to 45° C., preferably from about 0° C. to 25° C. The solution is stirred from about 5 to about 24 hours, preferably from about 10 hours to about 18 hours at a temperature of about 10° C. to about 30° C., preferably at a temperature of about 15° C. to 25° C.

In Reaction Sequence Ib, compound of formula (VII) is prepared by heating guanine (VI) with acetic anhydride, neat, at reflux for about 10 to 24 hours, preferably for about 12 to 18 hours.

N2,9-Diacetylguanine of formula (VII) is reacted with compound of formula (V) to form compound of formula (VIII) neat or in a solvent such as dioxane, sulfolane and the like in the presence of a catalytic amount of an acid such as bis(p-nitrophenyl)phosphate, toluenesulfonic acid, methylphosphonic acid or dichloroacetic acid, preferably bis(p-nitrophenyl)phosphate at a temperature of about 75° C. to 200° C., preferably at about 110° C. to 180° C. The reaction is generally carried out using 0.8 moles to 1.2 moles of compound of formula (V) to one mole of compound of formula (VII).

The benzyl protecting groups are removed from compound of formula (VIII) by catalytic hydrogenation to form compound of formula (IX). A catalyst such as palladium on carbon in a slurry is added to a solution of compound of formula (VIII) dissolved in a solvent such as aqueous methanol. Hydrogen is added to the solution at a pressure of 15 psi to 200 psi, preferably at a pressure of 30 psi to 80 psi.

Compound of formula (X) is prepared by deacetylating compound of formula (IX) with a base such as ammonia dissolved in an alcohol such as methanol. A solution of compound of formula (IX) and the base is stirred for about 5 hours to 36 hours, preferably for about 10 hours to 24 hours at a temperature of about 10° C. to 30° C., preferably at a temperature of about 15° C. to 25° C.

Compound of formula (X) may be esterified to the diacetate of formula (XI) by reacting compound of formula (X) with excess acetic anhydride, either neat or in a solvent such as dimethylformamide, dimethylacetamide and the like at room temperature for two to three days.

Compound of formua (XII) may be prepared by reacting compound of formula (XI) with phosphorus oxychloride according to the method described in J. Org. Chem. 28:945, 1963. Compound of formula (XI) is added to a solution of phosphorus oxychloride in N,N-diethylaniline at room temperature. The suspension is heated at reflux for 2 to 30 minutes, preferably from 2 to 5 minutes. The excess phosphorus oxychloride is removed and the product recovered by conventional means such as extraction with an organic solvent followed by chromatography.

Compound of formula (XII) may be further chlorinated by forming the diazo salt with sodium nitrite in hydrochloric acid as described in J. Org. Chem. 31:3258, 1966. To compound of formula (XII) in aqueous hydrochloric acid is added sodium nitrite in water at 0° to 5° C. The solution is diluted with water and the excess hydrochloric acid is neutralized with aqueous ammonia and compound of formula (XIII) is recovered by methods well known in the art such as extraction with an organic solvent followed by chromatography.

Compounds of formula (XIV) may be prepared from compounds of formulas (XII) and (XIII) by methods well known in the art. See, for example, "Heterocyclic Compounds--Fused Pyrimidines Part II Purines, Ed. D. J. Brown (1971) Wiley-Interscience" and U.S. Pat. No. 4,199,574 which patent is incorporated herein by reference. See preceding table for compounds of formula (XIV)a-j.

Compound of formula (XIVb) wherein A is hydrogen may be prepared by reacting a compound of formula (XII) with thiourea dissolved in a solvent such as isopropanol with heating at reflux for one to two hours. The thiourea adduct which forms is broken down with an alkali such as aqueous ammonia yielding the thio compound. The reaction also leads to the hydrolysis of the ester groups.

Compounds of formula (XIVa) wherein A is hydrogen and R is lower alkyl are prepared from compound of formula (XII) by treatment with an alcoholic solution of the appropriate alkali metal alkoxide such as sodium methoxide in methanol at room temperature or with mild heating.

Various compounds of formula (XIV) may be prepared from compound of formula (XIII). For example, compound of formula (XIVc) wherein A is acetyl is prepared by treating compound of formula (XIII) with sodium azide in a solvent such as ethanol:water, dimethylformamide, hexamethylphosphoramide and the like. The reactants are heated for two to 24 hours at 80° to 200° C. Compound of formula (XIVd), wherein A is hydrogen, are prepared by hydrogenating compound of formula (XIVc) using, for example, a palladium on charcoal catalyst.

Compound of formula (XIII) is converted to compound of formula (XIVe) wherein A is hydrogen by heating compound of formula (XIII) and ammonia dissolved in methanol in a bomb for 16 to 24 hours at 85° to 110° C. The above compound may be further ammoniated by heating compound of formula (XIVe) dissolved in liquid ammonia in a bomb for 24 to 48 hours at 110° to 150° C. to form compound of formula (XIVd) wherein A is hydrogen.

Another method of preparing compound of formula (XIVd) is by treating compound of formula (XIVe) with hydrazine and then with a cold solution of sodium nitrite to form compound of formula (XIVf) wherein A is hydrogen, which in turn is hydrogenated to the compound of formula (XIVd) using, for example, a palladium on charcoal catalyst.

The amino groups of compounds of formula (XIV) wherein R3 and/or R6 is amino may be alkylated to the secondary or tertiary amines by treatment with an alkyl halide such as methyl iodide. A preferred method for preparing the above alkylated amino compounds is by reacting a compound of formula (XIII) or (XIVe) with an alkyl or dialkyl amine.

Those compounds of formula (XIV) wherein A is acetyl may be hydrolyzed by methods well known in the art such as by acidic or basic hydrolysis.

Compounds of formulas (XIVg) and (XIVh) may be prepared by the hydrogenation of compounds of formulas (XII) and (XIVe) respectively using a hydrogenation catalyst such as palladium in the presence of a base such as magnesium dioxide.

Compound of formula (XIVi) wherein A is hydrogen is prepared by reacting compound of formula (XIVh) with sodium nitrite in acetic acid to form the 6-keto compound which in turn is chlorinated with a chlorinating agent such as phosphoryl chloride, phosphorous pentachloride and the like by methods well known in the art. The 6-chloro intermediate is treated with thiourea as described above.

Compounds of formula (XIVj) may be prepared, for example, by reacting compound of formula (XIVe) with methanolic hydrogen sulfide-ammonium carbonate as described in J. Org. Chem., 39(9):1256, 1974 or with sodium mercaptide in dimethylformamide as described in J. Med. Chem., 16(12):1381, 1973.

Compounds of formula (XIV) wherein R3 or R6 is thio may be alkylated with an alkyl halide such as an alkyl iodide in a solvent such as an alkanol at room temperature.

The following compounds of formula (XIV) wherein A is hydrogen, for example, may be prepared by one or a combination of the methods discussed above:

2-amino-6-methoxy-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-methylamino-6-ethoxy-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-amino-6-thio-9-(1,3-dihydroxy-2-propoxymethyl)-purine;

2-n-butylamino-6-thio-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-amino-6-methylthio-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-dimethylamino-6-methylthio-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2,6-diazido-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2,6-diamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-methylamino-6-amino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-amino-6-methylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2,6-di(methylamino)-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-chloro-2-amino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-chloro-6-methylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-azido-6-ethylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine

2-amino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-methylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

2-dimethylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-amino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-methylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-dimethylamino-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-thio-9-(1,3-dihydroxy-2-propoxymethyl)purine;

6-methylthio-9-(1,3-dihydroxy-2-propoxymethyl)purine; and

6-amino-2-thio-9-(1,3-dihydroxy-2-propoxymethyl)purine.

Compounds of formula (I) wherein R1 and/or R2 are -C(Y)OR7 may be prepared by forming an intermediate of formula (XV) (supra) wherein W is hydrogen or 1-carbonylimidazole and Wa is 1-carbonylimidazole or wherein W is hydrogen or 1-thiocarbonylimidazole and Wa is 1-thiocarbonylimidazole and reacting the intermediate with R7 OH wherein R7 is as defined above. When Y is oxygen, compounds of formula (X) or (XIV), wherein A is hydrogen, and 1,1'-carbonyldiimidazole, in a molar ratio of 1:10, preferably 1:3-5, are reacted with stirring in a solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine, hexane, acetonitrile, tetrahydrofuran, toluene and the like at room temperature to 70° C., preferably at 45° to 65° C. for 9 to 24 hours, preferably for 15 to 20 hours. After the removal of the solvent, the intermediate which may be a mixture of the mono and di carbonylimidazole of formula (XV) is reacted with the appropriate alcohol or amine, optionally in the presence of a catalyst such as 4-dimethylaminopyridine, with heating to 50° to 200° C., preferably from 75° to 125° C. for 12 to 48 hours, preferably for 18 to 36 hours. Compounds of formula (I) are isolated by methods well known in the art such as chromatography. Chromatography may also be used to separate the monocarbonate of formula (I) from the dicarbonate of formula (I). When Y is sulfur 1,1'carbonyldiimidazole is replaced with 1,1'-thiocarbonyldiimidazole in the above procedure.

1,1'-Carbonyldiimidazole is available from, i.a., Aldrich Chemical Co. The alcohols and amines used in the reaction are available or if not available may be prepared by methods well known in the art such as the alcohols may be prepared by reduction of the corresponding aldehyde or the amines may be prepared by the reduction of the corresponding nitro compound or by the reaction of ammonia with the appropriate hydrocarbon halide.

An alternative method for preparing the compounds of formula (I) wherein R1 and/or R2 are -C(O)OR7 is by reacting compounds of formula (X) or (XIV) wherein A is hydrogen with (R7 OC(O))2 O. The reactants in a solvent such as dimethylformamide and the like, in the presence of a catalyst such as 4-dimethylaminopyridine are stirred at room temperature to 50° C., preferably at room temperature, for 1 to 5 days, preferably for 11/2 to 4 days. Compounds of formula (I) are isolated by conventional methods such as chromatography.

Another method for preparing the compounds of formula (I) wherein R1 and/or R2 are -C(O)OR7 for all values of R7 is by first treating compound of formula (XI) or (XIV) wherein A is acetyl and R3 and/or R6 is amino with a trityl protecting agent such as triphenylmethyl chloride (trityl chloride), 4-methoxyphenyldiphenylmethyl chloride (mono-methoxytritylchloride) and the like. The trityl protecting agents are readily available from, i.a., Aldrich Chemical Co.. The reactants in a solvent such as dimethylformamide, pyridine, and the like with a catalyst e.g., 4-dimethylaminopyridine are heated at 40° to 70° C., preferably at 45° to 60° C. for 8 to 24 hours, preferably for 12 to 18 hours. The amino protected compound is isolated by conventional means such as crystallization and the acetate groups are hydrolyzed with a base, such as an alkali metal hydroxide, e.g., sodium hydroxide and potassium hydroxide, or with ammonium hydroxide. The dihydroxy compound and a catalyst such as 4-dimethylaminopyridine in pyridine is added dropwise to the appropriate hydrocarbyloxycarbonyl chloride either neat or in a solvent such as methylene chloride, dichloroethane and the like. The reactants are stirred at room temperature for 10 to 24 hours, preferably from 12 to 18 hours. The product is isolated by methods well known in the art such as chromatography. The amino protective groups are removed by treatment with an organic acid such as glacial acetic acid, trifluoroacetic acid, benzenesulfonic acid and the like with heating from room temperature to 100° C., preferably from 40° to 80° C. for one to twelve hours, preferably from one to five hours. The product is isolated by chromatography or crystallization.

The amino group(s) of the above described compound of formulas (XI) and (XIV) may also be protected by reacting the compounds with the acetal of N,N-dimethyl formamide available from, i.a., Aldrich Chemical Co. and then proceeding as discussed above.

The hydrocarbyloxycarbonyl chlorides are readily available or if not readily available may be prepared by reacting phosgene with the appropriate alcohol under reaction conditions well known in the art.

The monocarbonates of formula (I) may be prepared by reacting compounds of formula (X) or (XIV) wherein A is hydrogen with a trityl protective group as defined supra. The protective group reacts with the amino nitrogen if present and one hydroxy group. The unprotected hydroxy group is reacted with a hydrocarbyloxycarbonyl chloride by the method described supra. The protective groups are removed as described hereinabove.

Compounds of formula (I) wherein R3 and/or R6 are NHC(O)R8 may be prepared by heating compound of formula (I) wherein R3 and/or R6 is amino with the appropriate acid chloride in a solvent such as pyridine from 35° to 100° C., preferably from 50°-60° C. for 6 to 24 hours, preferably for 12 to 18 hours.

The following specific description is given to enable those skilled in the art to more clearly understand and practice the invention. It should not be considered as a limitation upon the scope of the invention but merely as being illustrative and representative thereof.

PREPARATION I Preparation of 1,3-Di-O-benzylglycerol

Sodium hydride (100 g (50% dispersion in mineral oil), 2.08 mol) was washed twice with 1 1 of hexane then dried under nitrogen. Dry dimethylformamide (1.5 1) was added. Benzyl alcohol (400 ml) was then added at such a rate to keep the temperature below 50° C. The addition took 2 hours. Epichlorohydrin (92.5 g, 1 mol) was then added dropwise over 0.5 hour with ice cooling in order to keep the temperature below 40° C. The solution was next stirred for 16 hours at 21° C. then for 2.5 hours at 50° C. The dimethylformamide was then removed by evaporation at reduced pressure. The oily residue was dissolved in 2.5 1 diethyl ether. The organic solution was washed with 2 1 of water, 2 1 of 2% hydrochloric acid, 2 1 of 1% sodium bicarbonate, and 1 1 of brine, dried over sodium sulfate, and concentrated to a brown oil. Distillation gave 147.8 g of 1,3-di-O-benzylglycerol (bp 170-180 C/l torr).

PREPARATION II Preparation of 1,3-Di-O-benzyl-2-O-chloromethylglycerol

Dry hydrogen chloride gas was bubbled for 1.5 hours into a solution of 1,3-di-O-benzylglycerol from Preparation I (15 g, 55 mmol) and paraformaldehyde (3.3 g, 110 mmol) in 175 ml of 1,2-dichloroethane at 0° C. The solution was then stored in a stoppered flask for 21 hours at 4° C. Next, the solution was dried over magnesium sulfate with warming to 21° C. then filtered and concentrated to give 17.5 g of 1,3-di-O-benzyl-2-O-chloromethylglycerol.

PREPARATION III Preparation of 2-O-Acetoxymethyl-1,3-di-O-benzylglycerol

To a solution of 1,3-di-O-benzyl-2-O-chloromethylglycerol from Preparation II (17.5 g, 55 mmol) in 400 ml of dimethlyformamide at 0° C. under a drying tube was added sodium acetate (6 g). The solution was then warmed to 21° C. and magnetically stirred for 15 hours. The solvent was removed by evaporation at reduced pressure and the oily residue dissolved in 1 pound of diethylether. The ether solution was washed once with 750 ml of water, two times with 250 ml of water, and once with 250 ml of brine, dried over sodium sulfate and concentrated to give 19 g of 2-O-acetoxymethyl-1,3-di-O-benzylglycerol as an oil.

PREPARATION IV Preparation of N2,9-Diacetylguanine

Guanine (20 g, 0.132 mol) was combined with 300 ml of acetic anhydride and the mixture heated at reflux for 16 hours. The mixture was cooled and the excess acetic anhydride removed by evaporation at reduced pressure. The residue was recrystallized from dimethyl sulfoxide to give 25.6 g of N2,9-diacetylguanine.

PREPARATION V A. Preparation of N2 -Acetyl-9-(1,3-dibenzyloxy-2-propoxymethyl)guanine

N2,9-Diacetylguanine from Preparation IV (15.61 g, 66 mmol), 2-O-acetoxymethyl-1,3-di-O-benzylglycerol from Preparation III (19 g, 55 mmol), and bis(p-nitrophenyl)phosphate (0.5g) were stirred together with 150 ml of diethylether. The solvent was removed by evaporation and the residue heated in a 175° C. oil bath for 1.5 hours under a stream of nitrogen. Column chromatography eluting with 1:9 methanol/methylene chloride followed by recrystallization from ethyl acetate afforded 4.76 g of N2 -acetyl-9-(1,3-dibenzyloxy-2-propoxymethyl)guanine, mp 145°-146° C.

B. Preparation of N2 -Acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine

To a solution of N2 -acetyl-9-(1,3-dibenzyloxy-2-propoxymethyl)guanine (4.62 g, 9.67 mmol) in 150 ml of methanol plus 40 ml of water was added 20% palladium hydroxide on carbon as a slurry in 10 ml of water. The mixture was hydrogenated on a Parr hydrogenator at 60 psi of hydrogen for 38 hours then filtered through celite and concentrated to a white solid. Recrystallization from methanol/ethyl acetate gave 1.4 g of N2 -acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine, mp 205°-208° C.

The mother liquor was further reduced with 10% palladium on carbon (1 g) in 150 ml of methanol plus 50 ml of water at 60 psi for 47 hours. The total yield of N2 -acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine was 2.11 g.

C. Preparation of 9-(1,3-Dihydroxy-2-propoxymethyl)guanine

N2 -Acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine (721.9 mg, 2.4 mmol) was stirred with 50 ml of methanolic ammonia solution (methanol saturated with ammonia at 0° C.) for 17 hours at 21° C. The solution was concentrated to a white solid and the residue recrystallized from water or methanol to give 582.3 mg of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, mp 250° C. d.

EXAMPLE 1 9-[1,3-Di(methoxycarbonyloxy)-2-propoxymethyl]guanine

A solution of 1.509 g of 9-(1,3-dihydroxy-2-propoxymethyl)guanine and 3.0 g of 1,1'-carbonyldiimidazole in 150 ml of dry dimethylformamide was stirred under a drying tube at 55° C. for 16 hours. A white precipitate developed. The dimethylformamide was removed at reduced pressure and the residue was treated with 200 ml of methanol at reflux for 2 hours under a drying tube. The solution was then cooled to 0° C. and filtered. The residue was recrystallized from methanol to give 1.576 g of 9-[1,3-di(methoxycarbonyloxy)-2-propoxymethyl]guanine, m.p. 204°-206° C.

EXAMPLE 2 A. 9-[1,3-Di(cyclopentyloxycarbonyloxy)-2-propoxymethyl]guanine

A solution of 0.50 g of 9-(1,3-dihydroxy-2-propoxymethyl)guanine and 1.6 g of 1,1'-carbonyldiimidazole in 75 ml of dry dimethylformamide was stirred under a drying tube at 55° C. for 17 hours. The dimethylformamide was removed at reduced pressure. The residue was treated with 20 ml of cyclopentanol and 50 mg of 4-dimethylaminopyridine and heated at 100° C. for 19 hours. The solution was concentrated and the residue chromatographed over silica gel eluting with a gradient of 1/9 to 1/5 methanol/methylene chloride to give 495 mg of 9-[1,3-di(cyclopentyloxycarbonyloxy)-2-propoxymethyl]guanine in the first cut which was recrystallized from methanol to give 0.37 g of the product, m.p. 211.5°-214° C.

B. Similarly, using the procedure in Example 1 or 2(A) substituting the appropriate alcohol for methanol or cyclopentanol and using the appropriate compound of formula (XIV), wherein A is hydrogen, the following compounds are prepared:

2-amino-6-methoxy-9-[1,3-di(ethoxycarbonyloxy)-2-propoxymethyl]purine;

2-methylamino-6-ethoxy-9-[1,3-di(n-propoxycarbonyloxy)-2-propoxymethyl]purine;

2-amino-6-thio-9-[1,3-di(n-butoxycarbonyloxy)-2-propoxymethyl]purine;

2-n-butylamino-6-thio-9-[1,3-di(n-hexyloxycarbonyloxy)-2-propoxymethyl]purine;

2-amino-6-methylthio-9-[1,3-di(n-octyloxycarbonyloxy)-2-propoxymethyl]purine;

2-dimethylamino-6-methylthio-9-[1,3-di(n-decyloxycarbonyloxy)-2-propoxymethyl]purine;

2,6-diazido-9-[1,3-di(ethenyloxycarbonyloxy)-2-propoxymethyl]purine;

2,6-diamino-9-[1,3-di(but-4-enyloxycarbonyloxy)-2-propoxymethyl]purine;

2-methylamino-6-amino-9-[1,3-di(oct-6-enyloxycarbonyloxy)-2-propoxymethyl]purine;

2-amino-6-methylamino-9-[1,3-di(dec-8-enyloxycarbonyloxy)-2-propoxymethyl]purine;

2,6-di(methylamino)-9-[1,3-di(cyclopentyloxycarbonyloxy)-2-propoxymethyl]purine;

6-chloro-2-amino-9-[1,3-di(cyclohexyloxycarbonyloxy)-2-propoxymethyl]purine

2-chloro-6-methylamino-9-[1,3-di(phenoxycarbonyloxy)-2-propoxymethyl]purine

2-azido-6ethylamino-9-[1,3-di(benzyloxycarbonyloxy)-2-propoxymethyl]purine;

2-amino-9-[1,3-di(methoxycarbonyloxy)-2-propoxymethyl]purine;

2-methylamino-9-[1,3-di(ethoxycarbonyloxy)-2-propoxymethyl]purine;

2-dimethylamino-9-[1,3-di(n-propoxycarbonyloxy)2-propoxymethyl]purine;

6-amino-9-[1,3-di(n-butoxycarbonyloxy)-2-propoxymethyl]purine;

6-methylamino-9-[1,3-di(n-pentyloxycarbonyloxy)-2-propoxymethyl]purine;

6-dimethylamino-9-[1,3-di(n-hexyloxycarbonyloxy)-2-propoxymethyl]purine;

6-thio-9-[1,3 di(n-octyloxycarbonyloxy)-2-propoxymethyl]purine;

6-methylthio-9-[1,3-di(n-decyloxylcarbonyloxy)-2-propoxymethyl]purine;

6-amino-2-thio-9-[1,3-di(ethenyloxycarbonyloxy)-2-propoxymethyl]purine; and

9-[1,3-di(n-octyloxycarbonyloxy)-2-propoxymethyl]guanine.

EXAMPLE 3 9-[1,3-Di(t-butoxycarbonyloxy)-2-propoxymethyl]guanine

A solution of 212 mg of 9-(1,3-dihydroxy-2-propoxymethyl)guanine and 56 mg of 4-dimethylaminopyridine in 5 ml of di-t-butyldicarbonate plus 10 ml of N,N'-dimethylformamide was stirred in a stoppered flask for 72 hours. The solution was then concentrated and the residue chromatographed (1/7 methanol/methylene chloride) to give 35.8 mg of 9-[1,3-di(t-butoxycarbonyloxy)-2-propoxymethyl]guanine following recrystallization from methanol, m.p. 192°-193° C.

EXAMPLE 4 9-(1,3-benzyloxycarbonyloxy-2-propoxymethyl)guanine

A mixture of 3.00 g of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, 300 mg of 4-dimethylaminopyridine, and 100 ml of acetic anhydride was vigorously stirred for 3 days at room temperature. The acetic anhydride was removed by evaporation at reduced pressure and the residue recrystallized from methanol to give 3.62 g of 9-(1,3-diacetyloxy-2-propoxymethyl)guanine, m.p. 237°-239° C.

A solution of 3.3 g of 9-(1,3-diacetoxy-2-propoxymethyl)guanine, 7.0 g of 4-methoxyphenyldiphenylmethyl chloride, 7.0 ml of triethylamine and 300 mg of 4-dimethylaminopyridine in 50 ml of dry dimethylformamide was heated with magnetic stirring at 50° C. for 15 hours. Methanol (5 ml) was added. The solution was then concentrated at reduced pressure to a brown oil which was chromatographed over silica gel eluting with 1:12 methanol:methylene chloride to give an oil. The oil was crystallized from ethyl acetate:hexane to give 5.42 g of N2 -(4-methoxyphenyldiphenylmethyl)-9-(1,3-diacetoxy-2-propoxymethyl)guanine, m.p. 139°-141° C.

4.0 G of N2 -(4-methoxyphenyldiphenylmethyl)-9-(1,3-diacetoxy-2-propoxymethyl)guanine in 100 ml of methanol plus 20 ml of concentrated ammonium hydroxide was magnetically stirred at 22° C. for 16 hours then at 50° C. for 2.5 hours. An additional 10 ml of ammonium hydroxide were then added and the solution stirred another 2.5 hours at 50° C. Next, the solution was concentrated at reduced pressure and the residual solid recrystallized from methanol:ethyl acetate to give 3.5 g of N2 -(4-methoxyphenyldiphenylmethyl)-9-(1,3-dihydroxy-2-propoxymethyl)guanine, m.p. 148°-151° C.

To a solution of N2 -(4-methoxyphenyldiphenylmethyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine (0.25 g), in pyridine (5 ml) at room temperature was added benzyloxycarbonylchloride (0.34 g) in 5 ml of dichloromethane. After 16 hours, the solution was evaporated and the residue chromatographed over silica gel (15% methanol in methylene chloride). Fraction A was recovered and the solvent evaporated to yield 150 mg of N2 -(4-methoxyphenyldiphenylmethyl)-9-[1,3-di(benzyloxycarbonyloxy)-2-propoxymethyl]guanine which was recrystallized from methanol, m.p. 152°-155° C. Fraction B was recovered and the solvent evaporated to yield 60 mg of N2 -(4-methoxyphenyldiphenylmethyl)-9-(1-hydroxy-3-benzyloxycarbonyloxy-2-propoxymethyl)guanine which was recrystallized from methanol, m.p. 193-198° C.

The 4-methoxyphenyldiphenylmethyl group is removed by treatment with an organic acid such as glacial acetic acid to yield 9-[1,3-di(benzyloxycarbonyloxy)2-propoxymethyl]guanine and 9-(1-hydroxy-3-benzyloxycarbonyloxy-2-propoxymethyl)guanine respectively.

EXAMPLE 5 A. 9-(1-Hydroxy-3-methoxycarbonyloxy-2-propoxy methyl)guanine

A solution of 84.5 mg of 9-(1,3-dihydroxy-2-propoxymethyl)guanine and 65 mg of 1',1'-carbonyldiimidazole in 5 ml of N,N-dimethylformamide was heated at 45° C. for 21 hours. The dimethylformamide was removed at reduced pressure and the residue boiled with methanol. The solution was concentrated and the residue chromatographed over silica gel eluting with a gradient of 1/7 to 1/4 methanol/methylene chloride. The first compound to elute was recrystallized from methanol to give 18.7 mg of 9-[1,3-di(methoxycarbonyloxy)-2-propoxymethyl]guanine. 9-(1-Hydroxy-3-methoxycarbonyloxy-2-propoxymethyl)guanine, which was eluted in the second cut, was recrystallized from methanol to give 26 mg of the product, m.p. 189°-190° C.

B. Similarly, using the above procedure in Part A substituting the appropriate alcohol for methanol and using the appropriate compound of formula (XIV) wherein A is hydrogen the following compounds are prepared:

2-amino-6-methoxy-9-(1-hydroxy-3-methoxycarbonyloxy-2-propoxymethyl)purine;

2-methylamino-6-ethoxy-9-(1-hydroxy-3-ethoxycarbonyloxy-2-propoxymethyl)purine;

2-amino-6-thio-9-(1-hydroxy-3-n-propoxycarbonyloxy-2-propoxymethyl)purine;

2-n-butylamino-6-thio-9-(1-hydroxy-3-n-butoxycarbonyloxy-2-propoxymethyl)purine;

2-amino-6-methylthio-9-(1-hydroxy-3-n-hexyloxycarbonyloxy-2-propoxymethyl)purine;

2-dimethylamino-6-methylthio-9-(1-hydroxy-3-n-octyloxylcarbonyloxy-2-propoxymethyl)purine;

2,6-diazido-9-(1-hydroxy-3-n-decyloxylcarbonyloxy-2-propoxymethyl)purine;

2,6-diamino-9-(1-hydroxy-3-ethenyloxycarbonyloxy-2-propoxymethyl)purine;

2-methylamino-6-amino-9-(1-hydroxy-3-but-4-enyloxycarbonyloxy-2-propoxymethyl)purine;

2-amino-6-methylamino-9-(1-hydroxy-3-oct-6-enyloxycarbonyloxy-2-propoxymethyl)purine;

2,6-di(methylamino)-9-(1-hydroxy-3-dec-8-enyloxycarbonyloxy-2-propoxymethyl)purine;

6-chloro-2-amino-9-(1-hydroxy-3-cyclopentyloxycarbonyloxy-2-propoxymethyl)purine;

2-chloro-6-methylamino-9-(1-hydroxy-3-cyclohexyloxycarbonyloxy-2-propoxymethyl)purine;

2-azido-6-ethylamino-9-(1-hydroxy-3-cyclohexyloxycarbonyloxy-2-propoxymethyl)purine

2-amino-9-(1-hydroxy-3-phenoxycarbonyloxy-2-propoxymethyl)purine;

2-methylamino-9-(1-hydroxy-3-benzyloxylcarbonyloxy-2-propoxymethyl)purine;

2-dimethylamino-9-(1-hydroxy-3-methoxycarbonyloxy-2-propoxymethyl)purine;

6-amino-9-(1-hydroxy-3-methoxycarbonyloxy-2-propoxymethyl)purine;

6-methylamino-9-(1-hydroxy-3-ethoxycarbonyloxy-2-propoxymethyl)purine;

6-dimethylamino-9-(1-hydroxy-3-n-propoxycarbonyloxy-2-propoxymethyl)purine;

6-thio-9-(1-hydroxy-3-n-butoxycarbonyloxy-2-propoxymethyl)purine;

6-methylthio-9-(1-hydroxy-3-n-hexyloxycarbonyloxy-2-propoxymethyl)purine; and

6-amino-2-thio-9-(1-hydroxy-3-n-octyloxylcarbonyloxy-2-propoxymethyl)purine.

EXAMPLE 6 A. 9-[1,3-Di(ethylaminocarbonyloxy)-2-propoxymethyl]guanine

A mixture of 0.500 g of 9-(1,3-hydroxy-2-propoxymethyl)guanine 1.588 g of 1,1'-carbonyldiimidazole, and 50 ml of N,N-dimethylformamide was stirred vigorously for 3.5 hours at 100° C. 15 M1 of 33% aqueous ethylamine was then added. After two hours the reaction mixture was concentrated at reduced pressure then chromatographed over silica gel eluting with 1/9 methanol/methylene chloride to give 9-[1,3-di(ethylaminocarbonyloxy)-2-propoxymethyl]guanine which was recrystallized to afford 0.33 g of the product, m.p. 198°-200° C.

B. Similarly, using the procedure as above in Part A substituting the appropriate amine for ethylamine and using the appropriate compound of formula (XIV), wherein A is hydrogen, the following compounds are prepared:

2-amino-6-methoxy-9-[1,3-di(methylaminocarbonyloxy)-2-propoxymethyl]purine;

2-methylamino-6-ethoxy-9-[1,3-(n-butylaminocarbonyloxy)-2-propoxymethyl]purine;

2-amino-6-thio-9-[1,3-di(n-hexylaminocarbonyloxy)-2-propoxymethyl]purine;

2-n-butylamino-6-thio-9-[1,3-di(n-octylaminocarbonyloxy)-2-propoxymethyl]purine;

2-amino-6-methylthio-9-[1,3-di(n-dodecylamino-2-propoxymethyl]purine;

2-dimethylamino-6-methylthio-9-[1,3-di(ethenylaminocarbonyloxy)-2-propoxymethyl]purine;

2,6-diazido-9-[1,3-di(cyclohexylaminocarbonyloxy)2-propoxymethyl]purine; and

2,6-diamino-9-[1,3-di(phenylaminocarbonyloxy)2-propoxymethyl]purine.

EXAMPLE 7 A. 9-[1,3-Di(methoxythiocarbonyloxy)-2-propoxymethyl]quanine

A solution of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (50 mg) and 1,1-thiocarbonyldiimidazole (175 mg) in 6 ml of dimethylformamide was heated at 50° C. for 16 hours. The dimethylformamide was evaporated at reduced pressure and the residue treated with methanol and a catalytic amount of 4-dimethylaminopyridine for 24 hours at room temperature. The solution was concentrated and the residue was chromatographed (1:5 methanol-methylene chloride) to give 10 mg of 9-[1,3-di(methoxythiocarbonyloxy)-2-propoxymethyl]guanine, m.p. 148-150° C. B. Similarly, using the above procedure in Part A substituting the appropriate alcohol for methanol and using compound of formula (XIV), wherein A is hydrogen, the following compounds are prepared:

2-methylamino-6-amino-9-[1,3-di(n-propoxythiocarbonyloxy)-2-propoxymethyl]purine;

2-amino-6-methylamino-9-[1,3-di(n-butoxythiocarbonyloxy)-2-propoxymethyl]purine;

2,6-di(methylamino)-9-[1,3-di(n-octyloxythiocarbonyloxy)-2-propoxymethyl]purine;

6-chloro-2-amino-9-[1,3-di(n-decyloxythiocarbonyloxy)-2-propoxymethyl]purine;

2-chloro-6-methylamino-9-[1,3-di(ethenyloxythiocarbonyloxy)-2-propoxymethyl]purine;

2-azido-6-ethylamino-9-[1,3-di(2-propenyloxythiocarbonyloxy)-2-propoxymethyl)purine

2-amino-9-[1,3-di(cyclopentyloxythiocarbonyloxy)-2-propoxymethyl]purine; and

2-methylamino-9-[1,3-di(benzyloxythiocarbonyloxy)-2-propoxymethyl) purine.

EXAMPLE 8

The following example illustrates the preparation of representative pharmaceutical formulations containing an active compound of formula (I) such as 9-[1,3-di(methoxycarbonyloxy)-2-propoxymethyl]quanine.

______________________________________A. Topical Formulation______________________________________Active compound          0.2-2  gSpan 60                  2      gTween 60                 2      gMineral oil              5      gPetrolatum               10     gMethyl paraben           0.15   gPropyl paraben           0.05   gBHA (butylated hydroxy anisole)                    0.01   gWater qs                 100    ml______________________________________

All of the above ingredients, except water, are combined and heated at 60° C. with stirring. A sufficient quantity of water at 60° C. is then added with vigorous stirring to provide 100 g of the cream formulation which is then cooled to room temperature.

The following formulation is useful for intraperitoneal (IP), subcutaneous (SC) and intramuscular (IM) injection.

______________________________________B. IP, SC and IM Formulation______________________________________Active compound        0.5    gTween 80               0.8    gBenzyl alcohol         0.9    g0.9% Saline solution qs                  100    ml______________________________________

The activecompound is finely micronized and added to Tween 80 and benzyl alcohol with stirring. A sufficient quantity of 0.9% saline solution is then added with stirring to provide 100 ml of the IP, SC or IM suspension which is filtered through a 0.2 micron membrane filter and packaged under sterile conditions.

______________________________________C. Tablet Formulation            Parts by weight______________________________________Active compound    200Magnesium stearate  3Starch              30Lactose            116PVP (polyvinylpyrrolidone)               3______________________________________

The above ingredients are conbined and granulated using methanol as the solvent. The formulation is then dried and formed into tablets (containing 200 mg of active compound) with an appropriate tabletting machine.

EXAMPLE 9

The exceptional antiviral activity of the compounds of the invention is illustrated by the following assay procedures:

The Herpes simplex virus 2 strain G for infection is prepared in HEp-2 cell cultures. Virus is adsorbed for 1 hour, fresh media is placed on the cells, and they are incubated at 35°C. until all cells are infected. The cell suspension is frozen at -70° C., thawed, and centrifuged to remove cell debris. The supernatant fluid is aliquoted and stored frozen at -70° C. until use. A 106.7 dilution of the supernatant fluid produces a 50% cell culture infective dose (CCID50) in HEp-2 cells and a 103.7 dilution produces a 50% lethal challenge (LC50) in mice.

Groups of 20 Swiss Webster female mice (15-17 gm), are challenged by intraperitoneal route using 0.2 ml of EMEM containing 10 LC50 /mouse of virus. Mice challenged with 100.5 more or less virus than the 10 LD50 challenge serves as a virulence control to assure the model is working properly.

Treatment with test compounds begins 6 hours post-challenge. The mice, divided into groups of 20, are administered the compounds in a suitable saline vehicle s.c. at 5 mg/kg, 10 mg/kg and 20 mg/kg. One group of 20 mice is used as a control group and administered the vehicle alone s.c. The treatment is repeated at 24, 48, 72 and 96 hours post-challenge.

Compounds of the instant invention show antiviral activity in the above test.

Claims (28)

What is claimed is:
1. A compound of the formula ##STR7## wherein R1 is hydrogen, --C(Y) OR7 or --C(O)NHR7 wherein R7 is alkyl of one to twelve carbon atoms, alkenyl of two to twelve carbon atoms, cyclopentyl, cyclohexyl, phenyl or benzyl;
R2 is --C(Y)OR7 or --C(O)NHR7 wherein R7 is as defined above;
Y is oxygen or sulfur;
R3 is hydrogen, halo, thio, lower alkylthio of one to six carbon atoms, azido, NR9 R10 wherein R9 and R10 are independently hydrogen or lower alkyl of one to six carbon atoms or --NHC(O)R8 wherein R8 is hydrogen, alkyl of one to nineteen carbon atoms or 1-adamantyl; and
(a) R6 is hydrogen, halo, lower alkoxy of one to six carbon atoms, azido, thio, lower alkylthio of one to six carbon atoms, --NR9 R10 wherein R9 and R10 are as defined above or -NHC(O)R8 wherein R8 is as defined above and R4 together with R5 is a bond; or
(b) R5 together with R6 is a keto group and R4 is hydrogen.
2. A compound of claim 1 wherein R3 is hydrogen or amino and R6 is hydrogen, thio or NH2 and R4 together with R5 is a bond with the proviso that R3 and R6 are not both hydrogen.
3. A compound of claim 2 wherein R3 is hydrogen, R4 together with R5 is a bond, R6 is amino, R1 and R2 are independently methoxycarbonyl which is 6-amino--[1,3-di(methoxycarbonyloxy)-2-propoxymethyl]purine.
4. A compound of claim 1 of the formula ##STR8## wherein R1 and R2 are as defined in claim 1.
5. A compound of claim 4 wherein R1 and R2 are --C(O)OR7 wherein R7 is as defined in claim 1.
6. A compound of claim 5 wherein R1 and R2 are independently methoxycarbonyl which is 9-[1,3-di(methoxycarbonyloxy)-2-propoxymethyl]guanine.
7. A compound of claim 5 wherein R1 and R2 are independently n-butoxycarbonyl which is 9-[1,3-di(n-butoxycarbonyloxy)-2-propoxymethyl]guanine.
8. A compound of claim 5 wherein R1 and R2 are independently t-butoxycarbonyl which is 9-[1,3-di(t-butoxycarbonyloxy)-2-propoxymethyl]guanine.
9. A compound of claim 5 wherein R1 and R2 are independently n-octyloxycarbonyl which is 9-[1,3-di(n-octyloxycarbonyloxy)-2-propoxymethyl] guanine.
10. A compound of claim 5 wherein R1 and R2 are independently cyclopentyloxycarbonyl which is 9-[1,3-di(cyclopentyloxycarbonyloxy)-2-propoxymethyl]guanine.
11. A compound of claim 5 wherein R1 and R2 are independently benzyloxycarbonyl which is 9-[1,3-di-(benzyloxycarbonyloxy)-2-propoxymethyl]guanine.
12. A compound of claim 4 wherein R1 is hydrogen and R2 is -C(O)OR7 wherein R7 is as defined in claim 1.
13. A compound of claim 12 wherein R1 is hydrogen and R2 is methoxycarbonyl which is 9-(1-hydroxy-3-methoxycarbonyloxy-2-propoxymethyl)guanine.
14. A compound of claim 12 wherein R1 is hydrogen and R2 is n-butoxycarbonyl which is 9-(1-hydroxy--n-butoxycarbonyloxy-2-propoxymethyl)guanine.
15. A compound of claim 12 wherein R1 is hydrogen and R2 is n-octyloxycarbonyl which is 9-(1-hydroxy--n-octyloxycarbonyloxy-2-propoxymethyl)guanine.
16. A compound of claim 12 wherein R1 is hydrogen and R2 is cyclopentyloxycarbonyl which is 9-(1-hydroxy-3-cyclopentyloxycarbonyloxy-2-propoxymethyl)guanine.
17. A compound of claim 12 wherein R1 is hydrogen and R2 is benzyloxycarbonyloxy which is 9-(1-hydroxy-3-benzyloxycarbonyloxy-2-propoxymethyl)guanine.
18. A compound of claim 4 wherein R1 and R2 are --C(S)OR7 wherein R7 is as defined in claim 1.
19. A compound of claim 4 wherein R1 and R2 are --C(O)NHR7 wherein R7 is as defined in claim 1.
20. A compound of claim 19 wherein R1 and R2 are independently ethylaminocarbonyl which is 9-[1,3-di(ethylaminocarbonyloxy)-2-propoxymethyl]guanine.
21. An antiviral pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a compound of the formula ##STR9## wherein R1 is hydrogen, -C(Y)OR7 or -C(O)NHR7 wherein R7 is alkyl of one to twelve carbon atoms, alkenyl of two to twelve carbon atoms, cyclopentyl, cyclohexyl, phenyl or benzyl;
R2 is --C(Y)OR7 or --C(O)NHR7 wherein R7 is as defined above;
Y is oxygen or sulfur;
R3 is hydrogen, halo, thio, lower alkylthio of one to six carbon atoms, azido, NR9 R10 wherein R9 and R10 are independently hydrogen or lower alkyl of one to six carbon atoms or --NHC(O)R8 wherein R8 is hydrogen, alkyl of one to nineteen carbon atoms or 1-adamantyl; and
(a) R6 is hydrogen, halo, lower alkoxy of one to six carbon atoms, azido, thio, lower alkylthio of one to six carbon atoms, --NR9 R10 wherein R9 and R10 are as defined above or --NHC(O)R8 wherein R8 is as defined above and R4 together with R5 is a bond; or (b) R5 together with R6 is a keto group and R4 is hydrogen.
22. An antiviral pharmaceutical composition of claim 21 which comprises a pharmaceutically acceptable carrier and a compound of the formula ##STR10## wherein R1 and R2 are as defined in claim 21.
23. A method of treating a viral infection in a warm blooded or cold blooded animal having a viral infection which comprises administering an effective amount of a compound of the formula ##STR11## wherein R1 is hydrogen, --C(Y)OR7 or --C(O)NHR7 wherein R7 is alkyl of one to twelve carbon atoms, alkenyl of two to twelve carbon atoms, cyclopentyl, cyclohexyl, phenyl or benzyl; R2 is --C(Y)OR7 or -C(O)NHR7 wherein R7 is as defined above;
Y is oxygen or sulfur;
R3 is hydrogen, halo, thio, lower alkylthio of one to six carbon atoms, azido, NR9 R10 wherein R9 and R10 are independently hydrogen or lower alkyl of one to six carbon atoms or --NHC(O)R8 wherein R8 is hydrogen, alkyl of one to nineteen carbon atoms or 1-adamantyl; and
(a) R6 is hydrogen, halo, lower alkoxy of one to six carbon atoms, azido, thio, lower alkylthio of one to six carbon atoms, --NR9 R10 wherein R9 and R10 are as defined above or --NHC(O)R8 wherein R8 is as defined above and R4 together with R5 is a bond; or
(b) R5 together with R6 is a keto group and R4 is hydrogen.
24. A method according to claim 23 of treating a viral infection in a warm blooded animal having a viral infection.
25. A method according to claim 23 of treating a viral infection in a cold blooded animal having a viral infection.
26. A method of claim 23 which comprises administering an effective amount of a compound of the formula ##STR12## wherein R1 and R2 are as defined in claim 23.
27. A method according to claim 26 of treating a viral infection in a warm blooded animal having a viral infection.
28. A method according to claim 26 of treating a viral infection in a cold blooded animal having a viral infection.
US06406583 1982-08-09 1982-08-09 Substituted 9-(1-0- or 3-0-monosubstituted or 1,3-Di-0-substituted propoxymethyl)-purines as antiviral agents Expired - Fee Related US4556659A (en)

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Applications Claiming Priority (17)

Application Number Priority Date Filing Date Title
US06406583 US4556659A (en) 1982-08-09 1982-08-09 Substituted 9-(1-0- or 3-0-monosubstituted or 1,3-Di-0-substituted propoxymethyl)-purines as antiviral agents
EP19830107818 EP0105135B1 (en) 1982-08-09 1983-08-08 Substituted 9-(1-0- or 3-0-monosubstituted or 1,3-di-0-substituted 1,3 dihydroxy-2-propoxymethyl) purines as antiviral agents
NZ20517183A NZ205171A (en) 1982-08-09 1983-08-08 Purine derivatives and antiviral compositions
DE19833370331 DE3370331D1 (en) 1982-08-09 1983-08-08 Substituted 9-(1-0- or 3-0-monosubstituted or 1,3-di-0-substituted 1,3 dihydroxy-2-propoxymethyl) purines as antiviral agents
HU279283A HU193530B (en) 1982-08-09 1983-08-08 Process for preparing 9-/3-0-monosubstituted or 1,3-di-0-substituted propoxymethyl/-guanine derivatives and pharmaceutical compositions comprising such active substances
AT83107818T AT25980T (en) 1982-08-09 1983-08-08 Substituted 9- (1-0- or 3-0-monosubstituted or 1,3-di-0-substituted-1,3-dihydroxy-2propoxymethyl) -purine as antiviral agents.
JP14485783A JPS5948483A (en) 1982-08-09 1983-08-08 Substituted 9-(1-o- or 3-o-monosubstituted or 1,3-di-o-substituted propoxymethyl)purines, manufacture, composition and treatment of viral infection
DK361383A DK361383D0 (en) 1982-08-09 1983-08-08 Substituted 9- (1-0-or 3-0 - monosubstituted or 1,3-d1-o-substituted-propoxymethyl) -purines and method for preparation thereof
FI832832A FI74006C (en) 1982-08-09 1983-08-08 Foerfarande Foer framstaellning of Antiviral substituted-9 (1-0- 3-0 eller eller monosubstituerad--1,3-di-0-substituted-propoximetyl) guaniiner.
KR830003708A KR890000811B1 (en) 1982-08-09 1983-08-08 Substituted-9-(1-0-0r 3-0- mono substituted or 1,3-di- 0-substituted propoxymethyl) purines and process for the preparation there-of
ZA8305799A ZA8305799B (en) 1982-08-09 1983-08-08 Substituted 9-(1-o-or 3-o-monosubstituted or 1,3-d1-o-substituted propoxymethyl)-purines as antiviral agents
NO832842A NO162469C (en) 1982-08-09 1983-08-08 Analogifremgangsmaate for preparing therapeutically active purine derivatives.
AU1768383A AU571451B2 (en) 1982-08-09 1983-08-08 Substituted 9-propoxymethylpurines
ES524811A ES524811A0 (en) 1982-08-09 1983-08-08 Process for preparing 9- (monosubstituted propoxymethyl 1-0 or 3-0 or disubstituted in 1.3 to 0) -purinas substituted as antiviral agents
IE186783A IE55843B1 (en) 1982-08-09 1983-08-08 Substituted 9-(1-0-or 3-0-monosubstituted or 1,3-d1-0-substituted 1,3-dihydroxy-2-propoxymethyl)purines as antiviral agents
US06744585 US4609661A (en) 1982-08-09 1985-06-13 Substituted 9-(1-O- or 3-O-monosubstituted or 1,3-di-O-substituted propoxymethyl)purines as antiviral agents
ES545261A ES8603186A1 (en) 1982-08-09 1985-07-16 Antiviral 9-1, 1-di:hydroxy-2-propoxy-methyl purine and guanine derivs

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Cited By (5)

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Publication number Priority date Publication date Assignee Title
US4609661A (en) * 1982-08-09 1986-09-02 Syntex (U.S.A.) Inc. Substituted 9-(1-O- or 3-O-monosubstituted or 1,3-di-O-substituted propoxymethyl)purines as antiviral agents
US4642346A (en) * 1985-06-24 1987-02-10 Syntex (U.S.A.) Inc. Anhydrous crystalline 9-(1,3-dihydroxy-2-propoxymethyl)guanine
US4880820A (en) * 1983-06-24 1989-11-14 Merck & Co., Inc. Guanine derivatives
US4897479A (en) * 1983-09-30 1990-01-30 Merck & Co., Inc. Arylsulfonyloxy purine intermediates
US6136813A (en) * 1989-03-03 2000-10-24 Beecham Plc Pharmaceutical treatment

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US4816447A (en) * 1981-08-26 1989-03-28 Merck & Co., Inc. Anti-viral guanine compounds
DE4002792A1 (en) * 1990-01-31 1991-08-01 Teves Gmbh Alfred Device for determining the nature of a druckuebertragungsfluessigkeit
GB2260319B (en) * 1991-10-07 1995-12-06 Norsk Hydro As Acyl derivatives of nucleosides and nucleoside analogues having anti-viral activity

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US4199574A (en) * 1974-09-02 1980-04-22 Burroughs Wellcome Co. Methods and compositions for treating viral infections and guanine acyclic nucleosides

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US4199574A (en) * 1974-09-02 1980-04-22 Burroughs Wellcome Co. Methods and compositions for treating viral infections and guanine acyclic nucleosides

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4609661A (en) * 1982-08-09 1986-09-02 Syntex (U.S.A.) Inc. Substituted 9-(1-O- or 3-O-monosubstituted or 1,3-di-O-substituted propoxymethyl)purines as antiviral agents
US4880820A (en) * 1983-06-24 1989-11-14 Merck & Co., Inc. Guanine derivatives
US4897479A (en) * 1983-09-30 1990-01-30 Merck & Co., Inc. Arylsulfonyloxy purine intermediates
US4642346A (en) * 1985-06-24 1987-02-10 Syntex (U.S.A.) Inc. Anhydrous crystalline 9-(1,3-dihydroxy-2-propoxymethyl)guanine
US6136813A (en) * 1989-03-03 2000-10-24 Beecham Plc Pharmaceutical treatment

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ES524811A0 (en) 1986-01-01 application
KR890000811B1 (en) 1989-04-08 grant
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KR840006007A (en) 1984-11-21 application
ES8603186A1 (en) 1986-01-01 application
FI832832A (en) 1984-02-10 application
FI74006C (en) 1987-12-10 grant
DK361383D0 (en) 1983-08-08 grant
FI832832A0 (en) 1983-08-08 application
ES524811D0 (en) grant
EP0105135A1 (en) 1984-04-11 application
ES8603185A1 (en) 1986-01-01 application
DK361383A (en) 1984-02-10 application
FI832832D0 (en) grant
FI74006B (en) 1987-08-31 application
EP0105135B1 (en) 1987-03-18 grant
ES545261A0 (en) 1986-01-01 application
DE3370331D1 (en) 1987-04-23 grant

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